The Doctor Weighs In

By Dov Michaeli MD, Ph.D

We all heard this refrain; drug addicts kicking the habit, only to go through a lifetime of a constant battle to stay clean.

Why is it so hard? Why is it getting progressively harder within days after quitting? Who is the “devil that made them do it”?

The received wisdom for many years was that the reward system in the brain, which is the seat of all manners of addiction, is driven exclusively by dopamine receptors. But frankly, this belief had some problems. Here is a big one: the dopamine system is geared to maintaining homeostasis, which is the property of a living organism to regulate its internal environment so as to maintain a stable, constant condition. For example, exposure of dopaminergic neurons to increased concentrations of cocaine results in increased effects inside the cells. To maintain a constant internal environment inside the cell, the neuron responds by reducing the number of dopamine receptors. However, when the drug effect wanes, the addict feels depressed, and to get the same “high” in the face of reduced density of receptors he’d have to take an even higher dose of the drug, which would, in turn, result in yet another lowering of receptor density on the cell membrane. This is the basis of addiction; progressively elevated doses of the stimulus needed to obtain the same effect. Dopaminergic neurons respond in the same fashion to cessation of the stimulus, only in the opposite direction – the density of receptors increases back to the normal level. If the dopamine neurons were the sole ones involved, then this should be the end of addiction syndrome. But we know that this is not true.

We know that recovered addicts have to constantly battle the urge to go back on the drug. The dopamine receptor system does not explain this behavior.

The neurobiological basis of faltering resistance

Marina Wolff wanted to see if the neurons bearing the glutamate receptor have something to do with the difficulties addicts encounter after withdrawing from the drug. So she and her colleagues examined the glutamate neurons in the nucleus accumbens, which is part of the reward system and is involved in motivation and learning. They trained rats to self-administer cocaine by poking their noses into a hole when given a cue. As expected, the rats’ cocaine-seeking beahvior was more pronounced 45 days after the cocaine supply was cut off than after the first day. Examining the rats’ nucleus accumbens, they found something totally unexpected. Compared with rats in early withdrawal, rats deprived of cocaine for 45 days had incredibly high levels of a glutamate receptor of an unusual composition (called GluR2-lacking AMPA receptors). This unusual receptor promotes an inordinately strong response to glutamate. Indeed, if the new glutamate receptors were blocked in rats 45 days after cocaine withdrawal, their response to drug cues was cut by almost 50%. The conclusion according to Marina Wolff is obvious: the neurons were making new receptors in response to withdrawal, which explains the increased response to cocaine cues.

The implications

The obvious implication is that this receptor should be a powerful target for drugs designed to help in withdrawal from drug addiction.

But did you notice that this craving after withdrawal and the increasing difficulty in resisting cues is also an affliction of serial dieters? Indeed, eating stimulates the reward system just like any recreational drug; and overeating has all the hallmarks of addictive behavior. So, the obvious next step is to examine the levels of this unusual glutamate receptor in animals trained to overeat. It may be the answer to the losing battles millions of people wage every day in a desparate attempt to avoid re-gaining the weight they had lost.

Lastly, one more thought. Until only very few years ago it was believed that complex behaviors could never be explained by “simple”chemistry. Books and articles were written about the uniqueness of the brain, as if it obeyed different laws of physics. Here we have a receptor of a known composition, whose level in the brain controls a complex behavioral pattern. Can the day be far when we would be speaking of all human behavior in molecular terms?

By Dov Michaeli MD, Ph.D

A few days ago my good friend Michael Millenson steered me to a video on a website called Ted.com (www.ted.com/talks/view/id/229). What I saw there was so profound and so exhilarating that I had to replay it several times. It was nothing short of an epiphany.

The view from within

"Neuroanatomist Jill Bolte Taylor had an opportunity few brain scientists would wish for: One morning, she realized she was having a massive stroke. As it happened – as she felt her brain functions slip
away one by one, speech, movement, understanding -- she studied and
remembered every moment. This is a powerful story about how our brains define us and connect us to the world and to one another".

To put things in context. In Biology we study cells, organs, and organisms. We study in detail their molecular makeup, their anatomy and their behavior. But there is one drawback: we are on the outside, trying to decipher the inside workings. We cannot physically get into a cell and observe its workings. So we do the second best, and use all kinds of tools and signs that suggest what is going on inside. We assume that these signs indeed reflect the inside reality. For instance, a cells recoils in response to a noxious stimulus. We can see under the microscope the scaffolding of a cell (a) organizing itself into cable-like structures(b), shortening on the one hand, elongating on the other, and the cell moves. We can inhibit the organizing of the scaffolding and abort the movement. So we ascribe the movement to the action of the molecular scaffolding—an eminently reasonable assumption.

But an assumption nonetheless. For instance, have we ruled out beyond a reasonable doubt that the chemical we used to inhibit the activity of the scaffolding hasn’t affected a yet undiscovered system, which could be the real driver of the cell’s response to the stimulus? We cannot get into the cell and directly observe the scaffold molecules tugging on the membrane; we stain the molecules that make up the scaffold so we can observe them, we measure their length and thickness before, during and after the movement, we inhibit their activity by adding inhibitory molecules or drugs. Based on all these observations we conclude that they are all consistent with the scaffold being responsible for cell movement. If it looks like a duck, walks like a duck, quacks like a duck—it must be a duck.

The pitfalls of observing from the outside

The danger is that these kind of observations basically amount to connecting the dots. And in the vast majority of cases, the picture we paint stands the test of accumulating evidence. But as we know from bitter experience, one can have a set of observations (the “dots”), and connect them in more than one way, many times in ways that serve an agenda rather than the truth. For a while there flourished a sociological specialty of “deconstructing” the sociology of science. These were non-scientists who looked at science from the outside, by interviews, observations of behaviors, interpretations of statements, "deconstruction" of writings—and then coming to conclusions about the workings of the scientific enterprise. Their theories were so laughable, so off the mark as to be outrageous, sometimes tinged with malice. I know it—I was on the inside,  they were on the outside looking in, through distorting lens as it were.

What does all this have to do with nirvana?

When we study the brain, we are basically outsiders looking in; we make reasonable assumptions, we arrive at reasonable conclusions. But we don’t directly experience the phenomena we are studying. That’s why I was so struck by Jill Bolte Taylor’s account of her left-sided stroke. Her left hemisphere slowly shut down while her right hemisphere continued to function more or less normally (the connections between the right and left hemispheres, called corpus callosum, were disrupted). Now, from countless observations and experiments we know that the left hemisphere is the seat of analytical thought, of memory, of language, of all our “executive” functions. The right hemisphere is the seat of our position in space, creativity, of art and music and the sense of wonder. But is that all? Dr. bolte Taylor's detailed account of the experience tells us that we were missing a deeper function of the right brain.

What she experienced was that unlike the left hemisphere, where boundaries of objects are sharply demarcated, the boundaries of things as perceived by the right hemisphere are fuzzy, they tend to merge with their surroundings. Objects appear misshapen, having indistinct boundaries. She felt that she is literally merging with the environment, becoming one with the universe. And in Buddhist writings, that’s the essence of what they call nirvana.

I know, I know, sounds like more “new age”-speak. Or just a malfunctioning brain akin to an LSD trip. But mind you, this is not your next door “flower child” speaking—this is a hard-nosed Harvard-trained neurobiologist chronicling her experience. This is a scientist observing from the inside!

The possibilities are endless

If true, then we can begin to understand the mechanism of meditation. We can possibly understand better the creative process, the deeper meaning of art, and music, and poetry. And maybe, just maybe, we could learn to become one with our environment, our world, and our fellow human beings.

By Dov Michaeli MD, Ph.D

It almost became a cliché: losing weight is relatively easy. That’s why you see so many “miracle diet” claiming astounding losses of weight. But why don’t we see miracle diets that tout maintenance of weight loss? Because this is the hard part of dieting. The reasons for that are both psychological and physiological, and the neurobiology of it is fascinating.

The neurobiology of diet failure

If you imagine the brain as made up of layers, the deeper ones are made of neurons that determine our response to environmental stimuli without us being conscious of it. If we come across an environmental cue that stimulates our feeding response, like a delicious looking chocolate cake, the response is an outpouring of hormones and peptides that signal to the brain: I’ve got to have that! Now, all this happens at speeds that are measured in milliseconds and microseconds—an astounding speed that eludes our consciousness. By the time our conscious thoughts take over, it is almost too late. These conscious thoughts travel in the cortex, the outer layer of the brain, at far slower speeds, measured in seconds. So by the time we try to exert some judgment (“I really shouldn’t”) the mood for the decision-making has already been formed. To counteract it is tough, and the longer we allow the “unconscious” pathways to prevail —the stronger the neuronal circuits that determine the response become. This is why it is so difficult to kick the habit, any habit, including overeating.

How can we win the battle of the brain?

The deeper, more primitive and fast moving neuronal circuits, can be restrained. By using the conscious, slow moving circuits again and again, over long periods of time, they become “unconscious”, and a lot more effective in intercepting our initial “bad” instincts. How this happens is a bit complicated and not completely known. But basically, they bypass the prefrontal cortex, the “decider” center in the brain. That is time-saving. Just imagine if every time we wanted to tie our shoe laces we had to recapitulate consciously the steps that we learned (consciously) in childhood. Repetition made it “unconscious”, and fast. Same for the multiplication table, for reading, for any learned activity that we repeat many times.

What does it have to do with weight maintenance?

A lot. If we could educate our conscious neurons to automatically resist that enticing chocolate cake, they would become “subconscious” and more effective in resisting the initial temptation. Yes, it requires repetition. And every iteration is a battle that has to be fought and won. I can understand St. Augustine ,  a 3^rd century bon vivant pagan who converted to Christianity, and who plaintively exclaimed: “Oh Lord, lead me not into temptation…but not quite yet”. The poor saint had to exile himself to the Syrian desert to deprive himself from the tempting “cues”of Rome. Even that fell short, and those “cues” came visiting and haunting. He could purge those unholy thoughts by flagellating himself—which is an extreme way of educating the subconscious. But it worked, and he could consequently devote himself to something more acceptable (to him): translating the Bible into Latin. And this brings up another aspect of “educating” the brain: the strength of the “educating” signal is as important as repetition.

But I am digressing. The “cue” that launched me into a journey of the brain was an article in the March issue of JAMA, titled “Comparison of Strategies for Sustaining Weight Loss”. This was a two-phase trial in which 1032 overweight or obese adults (38% African American, 63% women) with hypertension, dyslipidemia, or both who had lost at least 4 kg (9.2 lbs) during a 6-month weight loss program (phase 1) were randomized to a weight-loss maintenance intervention (phase 2). After the phase 1 weight-loss program, participants were randomized to one of the following groups for 30 months: monthly personal contact, unlimited access to an interactive technology–based intervention, or self-directed control.

The results: after 30 months , participants receiving personal counseling retained an average weight loss of 9.2 pounds, compared to an average of 7.3 pounds for those using the Web-based intervention and 6.4 pounds for those in the self-directed group.

After reading this blog we could have predicted this outcome. The personal counseling group received a stronger signal than the web-based group, and both received stronger “education” than the self-directed group.

You might think that a difference of 1.8 pounds between the two treatment groups may not justify the cost of personal counseling. Then think again: Each 2.2 pounds of weight loss can lower blood pressure by one point and can lower the risk of developing diabetes by 16 percent in high-risk adults . This is quite a reduction in health care costs.

 Is anybody  in Washington  listening?

By Dov Michaeli MD, Ph.D

Who hasn’t complained about loss of memory? With increasing frequency, I forget where I left my glasses, what’s her name? Where did I meet him? And for the hundredth time, what’s the name of this bird?

No, it is not incipient Alzheimer’s. I still write blogs, although that’s no proof of a sound mind. I manage a large drug development project, read the newspapers daily and am up on the latest political twist. So what’s going on?

Beware received wisdom

When I went to medical school (UCSF) I was struck by a paper I read claiming that 50% of what we were taught would be either obsolete, or plain wrong, within 5 years; amazing, but true, and not very reassuring to both physician and patient. One of the things I was taught with great certitude was that with age we progressively lose neurons, which make up the gray matter in the brain. True enough even today. It was then a no brainer to conclude that this loss of neurons is responsible for the creeping loss of cognitive function in the elderly. This tidbit of “information” turns out to be part of the 50% that is obsolete, and maybe even wrong.

The nerve cell

A neuron, like any other cell, has a “body”, enclosed by a membrane. It contains a nucleus, where DNA resides, mitochondria, the power plants that provide energy for the functions a neuron performs, and cytoplasm, where proteins are shuttled about and enzymes perform what they are supposed to. But then there is something unique to neurons: they have long projections, some of them inches long (which is enormous in the context of microscopically small cells). These long projections, called axons, serve two purposes: they serve as conduits for a traffic of neurotransmitters and other substances on their way out of the neuron. And, through tiny projections coming off their surface, called dendrites (small branches, in Latin), they make contact with other neurons around them. This is how information, in the form of electrical impulses, is passed around the brain along precisely demarcated circuits and over very long distances. The neuronal cell bodies, where the nucleus and the DNA reside, are the “brain” of the cell; they have a gray hue under the microscope—hence “gray matter”. The axons, on the other hand, are considered conduits only, very much like water or sewer pipes—no “brain” at all. They have a white hue, and are called the “white matter”.

Organization of the brain

The human brain can be divided into major functional regions, each responsible for different kinds of “applications,” such as memory, sensory input and processing, executive function or even one's own internal musing. The functional regions of the brain are linked by a network of white matter conduits. These communication channels help the brain coordinate and share information from the brain's different regions. White matter is the tissue through which messages pass from different regions of the brain.

Scientists have known that white matter degrades with age, but they did not understand how that decline contributes to the degradation of the large-scale systems that govern cognition.

So what’s new?

New research, published December 6, 2007, in the journal Neuron, begins to reveal how simply growing old can affect the higher-level brain systems that govern cognition. The research was conducted by Randy buckner’s group at the Harvard Medical School and the Howard Hughes Medical Institute. As Jessica Andrews-Hanna, a graduate student in Buckner's lab and the lead author of the study stated:
“The crosstalk between the different parts of the brain is like a conference call; we were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another.”
Buckner, Andrews-Hanna, and their colleagues looked at crosstalk in the brains of 93 people aged 18 to 93, divided roughly into a young adult group (18-34 years old) and an old adult group (60-93 years old). The older participants were given a battery of tests to measure their cognitive abilities—including memory, executive function and processing speed. Each person was studied using functional magnetic resonance imaging (fMRI) exams to measure activity in different parts of the brain. fMRI can precisely map enhanced blood flow in specific regions of the brain. Increased blood flow reflects greater activity in regions of the brain that are utilized during mental tasks.
For the task used in the Neuron study, subjects were presented words and were asked to decide whether each word represented a living (e.g., dog) or nonliving (e.g., house) object. Such a task requires the participants to meaningfully process the words.
Buckner's group explored whether aging in the older group caused a loss of correlation between the regions of the brain that — at least in young adults — engage in robust neural crosstalk.
They focused on the links within two critical networks, one responsible for processing information from the outside world and one, known as the default network, which is more internal and kicks in when we muse to ourselves. For example, the default network is presumed to depend on two regions of the brain linked by long-range white matter pathways. The new study revealed a dramatic difference in these regions between young and old subjects. “We found that in young adults, the front of the brain was pretty well in sync with the back of the brain,” said Andrews-Hanna. “In older adults this was not the case. The regions became out of sync and they were less correlated with each other.” Interestingly, the older adults with normal, high correlations performed better on cognitive tests.
According to the authors, it is inferred that in a young, healthy brain, signals are readily transmitted by white-matter conduits. As we age, those conduits are compromised. Depending on the networks at play, the result may be impaired memory, reasoning or other important cognitive functions. Buckner and Andrews-Hanna emphasized that other changes in the aging brain may contribute to cognitive decline. For example, cells' ability to express chemical neurotransmitters may also be compromised.

My take

1. Extremely important work. The dogma that “dropped neurons” is solely responsible for the cognitive deficits of normal aging simply did not make sense. First, the billions of neurons in the brain have plenty of capacity to make up for losses; we have a tremendous reserve. Second, the brain has the capacity to reroute specific information through alternative circuits if the original ones are compromised in any way. This is what underlies the phenomenon called “brain plasticity”, which is the basis for rehabilitation of stroke victims, or the educational strategies for dyslectic children.

2. This finding, like any in science, raises new questions. What is the nature of the disruption in the default network? Is it reduced number of axons due to neuronal death? Is it a functional defect in the conductive properties of the axons? Is the dysfunction generalized or restricted to specific pathways? What is the root cause of the changes? How can they be avoided?

What can we do about it now?

No doubt you have encountered claims of “brain rejuvenation”. Just work on your daily crossword puzzle, learn a new language, solve sudoku puzzles, stand on your head. The trouble with all these is that they work—but very specifically. If you do your daily crossword puzzles or sudoku you’d be good at them, but you will still forget names and misplace your car keys.

So far, the most convincing global change in the aging brain is reduced blood supply. Blood vessels either get occluded (atherosclerosis) or degenerate because of death of tissue they had supplied. Not surprisingly, the only strategy that proved effective in maintaining the overall integrity of cognitive function is, you guessed it, increase blood supply through aerobic exercise.

So throw away your sudoku puzzle or crossword puzzle and go out for a brisk walk or run. And don’t forget the keys to the house.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

On November 11 I read an Op Ed article in the New York Times titled “This is Your Brain on Politics”. Being interested in neurobiology, and an addict of all things political, I homed in like a laser beam: is this the holy grail of neuroscience? Are we capable of deciphering our innermost thoughts (in this case, political thoughts) using brain imaging techniques?

The article was written by three neuroscientists: Marco Iacoboni, Joshua Freedman and Jonas Kaplan of the University of California, Los Angeles, Semel Institute for Neuroscience; a communications professor, Kathleen Hall Jamieson of the Annenberg Public Policy Center at the University of Pennsylvania; and Tom Freedman, Bill Knapp and Kathryn Fitzgerald of FKF Applied Research.

The experiment

The authors used functional magnetic resonance imaging (fMRI) to scan the subjects' brains while they viewed images of political candidates. This imaging technique can be used to measure changes in oxygenated blood and hence to infer changes in metabolic activity in different parts of the brain. Some parts of the brain reliably alter their activity under certain conditions, and scientists have used this fact, along with information drawn from other techniques in both humans and animals, to document which brain area is associated with which cognitive function. For example, greater activity in the insula is often reported when people experience disgust, whereas more activity in the amygdala is reported when people are anxious.

While in the scanner, the subjects viewed political pictures through a pair of special goggles; first a series of still photos of each candidate was presented in random order, then video excerpts from speeches. Then they were shown the set of still photos again. On the before and after questionnaires, subjects were asked to rate the candidates on the kind of 0-10 thermometer scale frequently used in polling, ranging from “very unfavorable” to “very favorable.”

The results

Here are some excerpts from the findings:

1. Voters sense both peril and promise in party brands. When we showed subjects the words “Democrat,” “Republican” and “independent,” they exhibited high levels of activity in the part of the brain called the amygdala, indicating anxiety. The two areas in the brain associated with anxiety and disgust — the amygdala and the insula — were especially active when men viewed “Republican.” But all three labels also elicited some activity in the brain area associated with reward, the ventral striatum, as well as other regions related to desire and feeling connected. There was only one exception: men showed little response, positive or negative, when viewing “independent.”

2. Emotions about Hillary Clinton are mixed. Voters who rated Mrs. Clinton unfavorably on their questionnaire appeared not entirely comfortable with their assessment. When viewing images of her, these voters exhibited significant activity in the anterior cingulate cortex, an emotional center of the brain that is aroused when a person feels compelled to act in two different ways but must choose one. It looked as if they were battling unacknowledged impulses to like Mrs. Clinton.

Subjects who rated her more favorably, in contrast, showed very little activity in this brain area when they viewed pictures of her.

This phenomenon, not found for any other candidate, suggests that Mrs. Clinton may be able to gather support from some swing voters who oppose her if she manages to soften their negative responses to her. But she may be vulnerable to attacks that seek to reinforce those negative associations.

7. John Edwards has promise — and a problem. When looking at pictures of Mr. Edwards, subjects who had rated him low on the thermometer scale showed activity in the insula, an area associated with disgust and other negative feelings. This suggests that swing voters’ negative emotions toward Mr. Edwards can be quite powerful .

Oh, Yeah?

Take John Edward’s “problem”, for example. Is the fact that the insula showed higher activity dooms his campaign? increased activity in any brain area is rarely exclusive to any one function. That insula activity did not necessarily mean the subjects were disgusted. Insula activity has also been associated with drug craving, the taste of chocolate, pain and the quality of orgasm (!). Not necessarily such bad news after all.

This is not “junk Science”; it is purely junk

The authors wouldn’t dare publish such an article anywhere else but on an Op-Ed page; a peer-reviewed journal would send a rejection notice by return mail.

Here is a response of Brandon Keim in Wired science magazine:

“As science, it was a joke. As political theory, it was shallow. As an op-ed, it should have been thrown out at first glance. Uninformed opinion is tolerable in an editorial, but not when it purports to be validated by bad science .”

And the response of 14 heavy-weight neuroscientists:

“The results reported in the article were apparently not peer-reviewed, nor was sufficient detail provided to evaluate the conclusions.

As cognitive neuroscientists, we are very excited about the potential use of brain imaging techniques to better understand the psychology of political decisions. But we are distressed by the publication of research in the press that has not undergone peer review, and that uses flawed reasoning to draw unfounded conclusions about topics as important as the presidential election .”

Why shame on the NYT?

After all, you might think, why not open a window of expression to all scientific observations, valid or not? We do publish rubbish like “intelligence design”, or “creationist theory” side by side with “evolutionary theory”. As chief Justice Brandeis famously said: sunshine is the best disinfectant. But as Nature magazine stated: “What is troubling about the NYT is that the results described in the op-ed are apparently the claims of a commercial product posing as a scientific study. This is only partially transparent. Three of the authors list their affiliation with FKF Applied Research, a company based in Washington DC that is notorious for using similar brain-scan analysis to conclude which TV adverts (pardon the Britishism) aired during a major sporting event were most effective. In its own words, the company is a "business intelligence firm selling fMRI brain scan-based research to Fortune 500 companies".

More troubling for a mainstream newspaper that prides itself on its balanced reporting is the absence of declarations from three other authors. Rightly listed as affiliated to a neuroscience institute at the University of California, Los Angeles, one is also a co-founder of FKF Applied Research and all three, according to a previous publication, have benefited from funding from the company.”

Any harm done?

Yes, and yes. First, harm was done to the reputation of Science as a self-monitoring and self-correcting mechanism, whose only fealty is to the Truth. It gives credibility to political hacks in Congress and other branches of the government who claim that global warming is a figment of statistical models conjured up by “UN scientists”, that Evolution is “only a theory” propagated by atheist-scientists, that the medical harm of tobacco smoking is not supported by credible evidence, and so on and so on. In a day when the assault on science has not reached such a magnitude since the days of the medieval church—we don’t need to provide more weapons for their armamentarium.

And second: The “Twinkies Defense”, used in supervisor Dan White’s defense of his murder of S.F. mayor John Moscone and supervisor Harvey Milk, was a harbinger of things to come. This junk science was presented to the court by a psychologist-“scientist”. Brain imaging “evidence” is now being presented in court by hired gun-“neuroscientists”. Genetic information is being twisted beyond recognition in the service of racists and other malevolent rabble.

This is why an article such as this one is not just an innocent romp through neuroscience and politics, maybe even with a faint sense of humor. It is harmful, and shame on the NYT for publishing it.

Dov Michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

Phew…that was something. We ate and we ate, and drank and drank—I thought we are going to burst. Literally. I hope everybody in our Thanksgiving party (over 30 people) survived intact. Being a doctor, and a worrier, the thoughts of what could go wrong were never quite banished by the pleasures of gluttony. What dangers were going through my mind?

The burst stomach

Have you ever seen a snake swallowing a whole turkey? You can actually see the poor creature traveling through the long intestines of the tubular glutton. Well, a burst stomach is extremely rare, and happens only in rare conditions where the brain center controlling hunger and satiety is malfunctioning. Normal stomach capacity is about 8 cups, although it can range form 4 to 12, according to Dr. Edward Saltzman of Tufts Medical School, quoted in a New York Times article on the hazards of Thanksgiving. But for us regular gluttons, there are more common dangers lurking in stuffing our faces.

Heart attacks

This is probably the most serious problem of serious overeating. Here is what happens:

A normal meal of about 1500 calories sits in the stomach 1-3 hours, depending on the amount of fat in the diet; fat slows down stomach emptying. How is this night different from all other nights? The average American consumed yesterday 4500 calories and 229 grams of fat, according to the Calorie Control Council (full disclosure: they represent the makers of low-calorie foods). The average time to empty this humongous amount of fatty food is 8 hours. This in itself can cause only a sensation of fullness (loosen your belts) and flatulence (leave the room, please). But what goes on in your physiology is more serious: in order for the stomach and intestines to perform their job, they get an increased supply of blood coursing through the arteries and veins that supply them. This blood is diverted from vital organs such as the heart (vital for all of us) and the brain (less vital for some people I know). Now if instead of 1-3 hours the blood has to take an 8 hour detour, and a lot more blood diverted, to boot, and you can see the stress the heart and the brain are undergoing. In fact, if the blood supply to the heart is marginal to begin with, this massive diversion of blood volume will tip the balance and result in a heart attack.

To add insult to injury, the high fat content in a typical Thanksgiving meal results in a massive influx of lipids and triglycerides into the blood. This situation, called hyperlipidemia and hypertriglyceridemia, causes an increase in platelet aggregation. Those tiny cells, when sticking together to form a platelet clot, can cause blockage of the coronary precipitating, yes you guessed it, a heart attack. The combination of reduced volume of blood flow to the heart, and the increase in blood coagulability is more than additive; the risk is not 1+1=2, it is more like 1+1=10.

The gall of it all

In order to absorb dietary fat our digestive system needs to break it up into microscopically small particles. This is accomplished by the bile, a juice flowing from the gallbladder. Sometimes, the solids in the bile precipitate out and form gallstones. They can then occlude the bile duct, the narrow outlet from the gallbladder to the small intestine. When there is a lot fat in the diet, the hormone chlecystokinin signals that a large amount of bile is required. But if the bile duct is occluded the bile backs up, and the result is excrutiating abdominal pain that may mimic the pain of a heart attack.

What about the brain?

Here the consequences can be just as serious. The reason we feel drowsy after a heavy meal is that blood supply to the brain is reduced. This in itself never killed anybody. But add to this the amount of alcohol we consume with the meal—and put us behind the wheel, and you can see why the accident rate is sky high and Highway Patrol is out in force on Thanksgiving Day.

Before you rush to your computers to berate me for omitting your favorite culprit or theory, here is one subject you shouldn’t bother about: the urban legend that the amino acid tryptophan is the culprit of the meal-induced drowsiness. Tryptophan is indeed the precursor of melatonin, the sleep-inducing hormone. But the amounts required to increase significantly the level of melatonin are much higher than even the most outrageously gluttonous feast can provide.

Now that I told you how badly we behaved yesterday, did I restrain myself? As they say in New York, fuggeddaboudit; I stuffed my face and enjoyed every calorie of it. Today, though, starts the hard task of atoning for my sins. But I enjoyed it while it lasted. I hope you did too.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

An article in the Sept. 17 2007 issue of Time magazine tweaked my interest. In it the author, John Cloud, argues that the recent crop of Republican homosexual legislators deserves our understanding of their weakness, rather the opprobrium of hypocrisy. To quote Cloud, he is offering “a moistly liberal request: Can we have a moment of pity for moralizers who fall?”

His argument runs as follows:

“Hypocrisy is among the most universal and well-studied of psychological phenomena, and the research suggests that Craig, Haggard and the others may be guilty not so much of moral hypocrisy as moral weakness. The distinction may sound trivial at first, but as a society, we tend to forgive the weak and shun the hypocritical.

Assume for a moment that Craig and Haggard actually believed what they said--that homosexuality is sin. They spent most of their lives fighting for the conservative cause. But in Craig's case, the Idaho Statesman has published allegations that there were at least three other slipups involving men, beginning in 1967. What if, like the radio host who gets fat but commits to losing weight, the moralizers were trying through their "pro-family" endeavors to expiate their lustful sins? You may think they are wrong about homosexuality (I do), but that doesn't make them hypocrites.”

With all due respect, this argument is not “moistily lliberal”, it is down right wrong on scientific and moral grounds.

What did  Larry (wide stance) Craig actually say? Here is one quote: “It is important for us to stand up now and protect traditional marriage, which is under attack by a few unelected judges and litigious activists”. Here is a man who married a woman and for decades fought against equality for gays.

So that we are not accused of picking on one unfortunate soul, remember Mark Foley?

Here is what he said: “For those pedophiles and predators across this country that have harmed or are considering harming a child, let me tell you that you are on notice… Your days in the shadows are over.” How prophetic, and how poetically just. This is the stuff Greek tragedies are made of.

Is it classical hubris, or is it hypocrisy?

The classical Greeks did not have Freud to kick around. They attributed human failings to hubris, a cardinal sin in the eyes of the Olympian gods. And the retribution that followed was swift and merciless. No moistily liberal excuses for them.

Two thousand years later, Shakespeare took a more nuanced approach to human failing. The hubris of the proud and vain King Lear had to be paid for, and dearly. But the process of suffering cleansed him of his hubris and opened his heart to love. His tragic death broke the hearts of millions.

Enter Freud, about 300 years later. His original psychoanalytic theories have been largely discredited, but the psychobabble residue they have left behind is still with us. Hence the “psychological” and moral sleight of hand a la Cloud: these people are not hypocritical at all, they are just weak.

Neurobiology refutes this argument

A recent review in Science (“Social Decision-Making: Insights from Game Theory and Neuroscience”) makes the point that social decision-making is controlled by a complex network of centers in the brain. The middle area of the prefrontal cortex (MPFC) and the area just below it (the orbitofrontal cortex, or OFC) constitute the “executive center”, making final judgments that balance inputs from the anterior and posterior cingulate cortex (ACC and PCC) which are the reward areas, and from the amygdala and the insula (AMY and INS), which process the more primitive urges, such as fright, aggression, hatred, rage, etc (Dr. Freud, is this the anatomical locus of your concept of the “subconscious”?).

What is important about this new research is showing the part of emotions in the overall mix of inputs into our decision-making. And this brings us to a potential explanation for what is called “cognitive dissonance”. What is meant by that is the nagging, and sometimes profound discomfort we feel when our behaviors don’t align with our beliefs. Our prefrontal cortex will keep nagging us, disturbing our peace of mind, interfere with our sleep, afflict us with unpleasant dreams—until we bring our behavior into alignment with our beliefs, which in reality are the products of the judgments made in the prefrontal cortex.

I accept that if you say one thing and then do another, the cognitive dissonance you will suffer is a result of your weakness. But when you do one thing and then say another—this is no weakness, this is willful hypocrisy. Larry Craig did not become a homosexual last month or last year. He was probably gay before he was a senator. Science tells us that he probably was born a homosexual. Mark Foley didn’t discover children when he first saw a congressional intern. They were most likely the objects of his desire decades ago.

Which leads me to the most “unmoistily liberal” conclusion: these people are hypocritical. The excuse of weakness or “the devil made me do it” doesn’t wash: Your prefrontal cortex warned you time and again that your behavior is reprehensible; you chose to ignore it. You did one thing and then chose to say or do something antithetical, in order to advance your political career. If the consequences began and ended with you alone—nobody cares. But your decision-making had social consequences. Your words, votes, actions— they inflicted grave harm on innocent people who have done you no wrong.

Dov Michaeli MD, Ph.D is in biotech and brooks no B.S.

By Dov Michaeli MD, Ph.D

“Methought I heard a voice cry ‘Sleep no more!

Macbeth does murder sleep’—the innocent sleep,

… The death of each day’s life, sore labor’s bath,

Balm of hurt minds, great nature’s second course,

Chief nourisher in life’s feast”

Macbeth, William Shakespeare, 1600 AD.

Four hundred years later UC Berkeley scientists used brain imaging techniques to explain Lady Macbeth’s sleep-deprived brain descent into the darkness of insanity. They studied 26 young adults, half of whom were kept awake for 35 hours straight and the other half were allowed a normal night’s sleep in that same time period. Their brain was then studied using fMRI imaging. This technique shows the blood flow to different areas of the brain, and by extension, their state of activation.

What did they find?

The amygdala is the area in the brain that deals with unpleasant (or aversive) emotions, and puts the body on alert to protect itself. For instance, feelings of fear or rage are processed there. In the sleep-deprived subjects this area “lit up”, showing a high activation state.

On the other hand, the prefrontal area is responsible for tamping down those feeling, of adding some rationality into the mix; in a word, the outcome of its intervention is what we call ‘judgment’. In the sleep-deprived subjects the level of activation of the prefrontal cortex was significantly reduced.

Subjects who had gotten a full night of sleep showed normal brain activity.

This is not surprising to anybody who has experienced sleep deprivation, and that’s essentially all of us. Who hasn’t experienced the easy irritability, or alternatively the giddiness, that come after a sleepless night? Or the compulsive and nervous eating? Or the feeling that your “resistance is down” and that you are prone to a viral cold? These feelings are not “all in you head”. Sleep deprivation has been shown to affect emotional well-being, to alter metabolic control, and to adversely affect the part of the immune response (called innate immunity) that protects us from bacterial and viral infections.

There may be more to it

If the capacity to tamp down negative thinking is impaired, it opens up the possibility of a connection to psychiatric disorders like depression and anxiety. If you think of it, both of these disorders are a reflection of inappropriate or exaggerated negative response to a stressful event. Such events need not be dramatic, they could be quite trivial. A not-so-good grade at school, perceived slight from a friend, a critical remark by a coworker—all these can precipitate depression or anxiety. And the brain mechanism is identical to that of sleep deprivation: an imbalance between the negative messages flowing from the amygdala, and the moderating and rationalizing effect of the prefrontal cortex.

America the sleepless

How much sleep do we need? It varies with age and overall health. Most adults require 7- 8 hours a night. Older people may need 5-6 hours. Teenagers may require an hour or so more. Now consider the following:

· The National Sleep Foundation poll found that in 1998 35% of adult Americans got at least 8 hours of sleep a night. In 2005 this figure dropped to 26%.

· About 40% of Americans get less than 7 hours of sleep.

· 75% reported having some sleep disorder one or two nights a week.

These are sobering statistics. I can’t help but wonder if our chronic sleep deprivation is not a contributing factor to our elevated level of societal rancor, increased violence, our deteriorating civility, and our increased rate of diagnosed psychiatric disorders such as chronic depression, anxiety and sociopathic behavior.

Sleep has become synonymous with sloth in our “on the go” society. It would take more than academic studies to change this culture. We need nothing less than a paradigm shift in our outlook on life.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

The question of what makes us "human" has occupied philosophers since  Aristotle. And the well worn, but profound statement of 17th century French philosopher Descartes "I think, therefore I am" or in Latin "cogito ergo sum" (he actually wrote it if French: "Je pense, donc je suis"), has formed the basis for modern Western philosophy to this day. Today, thinking is one of the basic traits attributed to being human. And one of the of the pillars of thinking is language and speech, the ability to express our thoughts. From here, it is only a logical skip and hop to the assumption that Homo sapiens' uniqueness resides in its aqcuisition of the capacity for speech. In fact, molecular biologists discovered that a gene responsible for speech, FOXP2, has undergone mutations in two areas. And it is these mutations that endowed us with the capacity for speech while the chimpanzee, which does not  have these mutation, has no capacity for complex speech and by extension, for expressing ideas.

This finding is really mind boggling. Just stop and think about it for a minute: a couple of completely random mutations in a specific gene have such profound effects so as to transform a non-thinking species into a thinking species - one which,  in time, would grow to dominate not only the world, but also the genetic processes that brought about the critical mutations in the first place. It is nothing short of of amazing. No wonder some people would see the hand of an "intelligent designer" in accomplishing this simple, yet elegant, feat.

But wait, things are not that simple

The New York Times reports on October 19 2007:

Neanderthals, an archaic human species that dominated Europe until the arrival of modern humans some 45,000 years ago, possessed a critical gene known to underlie speech, according to DNA evidence retrieved from two individuals excavated from El Sidron, a cave in northern Spain.  The new evidence stems from analysis of a gene, called FOXP2, which is associated with language. The human version of the gene differs at two critical points from the chimpanzee version, suggesting that these two changes have something to do with the fact that people can speak and chimps cannot.

The genes of Neanderthals seemed to have passed into oblivion when they vanished from their last refuges in Spain and Portugal some 30,000 years ago, almost certainly driven to extinction by modern humans. But recent work by Svante Paabo, a biologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has made it clear that some Neanderthal DNA can be extracted from fossils.

Dr. Paabo, Dr. Johannes Krause and Spanish colleagues who excavated the new bones say they have now extracted the Neanderthal version of the relevant part of the FOXP2 gene. It is the same as the human version, they report in today's issue of Current Biology.

What's the big deal?

We used to think of our cousins, the Neanderthals, as primitive, cultureless cave dwellers, who became extinct because they were just too dumb to compete with us, the intelligent creatures chosen to inherit the earth.

Bit by bit evidence is emerging that they were not primitive at all, compared with contemporary Homo sapiens. They made tools, just like us. They even made jewelry, similar to ours. What that implies is not only artistic capacity, but also the capacity to think abstractly; jewelry is fundumentally a symbolic expression of feelings, of desire to attract the opposite sex, and of social status. So not only were our "poor cousins" quite sophisticated, they must have had some kind of social hierarchy--just like us.

Now, we know that they could communicate using language. FOXP2 is critical for the capacity to speak, but it would be an oversimplification to assume that that it is the only gene involved in speech. Nevertheless, what we know today is that speech did not make us unique, and that we were not exclusively endowed with intelligence, with abstract thinking, or with a sense of community and society.

FOXP2: what does it do? 

When we talk about the endowment of the capacity for language, don't you think about some complex neurological circuits in the brain, somehow miraculously transformed into the the substrate on which grammar and syntax grow?  I always felt that there is something really abstract, almost magical about the acquistion of the capacity to express ourselves through speech.

Puff, the magic dragon

Like all other magical things, when we learn the mechanics of the "trick", the awe is replaced with a feeling of let down; is that all there was to it? I thought about it today, as my wife and I toured the Johnson Space Center in Houston, saw Mission Control in its true dimensions (much smaller  and drab than we saw on "Appolo 13" or on TV), and the Astronaut Training Center. The latter was especially deflating. I always had a sense of wonder about those competent, knowledgable, daring, cool guys who seemingly could do anything under the most extreme circumstances. They were bigger than life, they were super human. Until we saw the mundane mechanics of their training. It was nothing more sophisticated than mastering certain skills in handling all kinds of hardware, not much more complicated than operating a crane, or learning to drive. Of course, some of the operations are complex, some require extreme eye-hand coordination-but basically, given the ten-year training period, any school teacher could do it. Astonishingly, you don't even have to be a pilot.

What does all this have to do with FOXP2?

Unlike the magical powers I was ready to attribute to this gene, it probably is  involved in control of rapid motor movement , and the mutations that allowed us to speak simply enabled us to utter words, which require extremely rapid and delicately controlled  muscle action.When a chimp sees something breathtaking he may sit, watching in awe, silently (or maybe a grunt or two). We, on the other hand, may wax poetic about it. But the somewhat disappointing difference is not abstract or magical at all, but purely mechanical--we have the mechanical capacity to give immediate expression to our thoughts. And so did our Neanderthal cousins.

What about dolphins, and whales? We still don't know, but I am sure that their FOXP2 gene is being looked at.

Are there other species that have the mutations in FOXP2? Yes. Echolocating bats have it, and it makes sense: the bat has to rapidly respond to a continuous stream of sensations (sonar pulses), and respond appropriately. Bats that are not echolocating do not have these enabling mutations.

Confused? Don't feel bad about it-- so is everbody else. The story of language is still unfolding. What we are witnessing is the uncovering of the mysterious magic of language, and when the details come to light, inevitably some of the mystery and its magical quality will dissipate.

Dov Michaeli MD, Ph.D is in the Biotech industry  

By Dov Michaeli MD, Ph.D

Have you ever wondered why do people reach for food, any food, when they are under stress? With most people, this stress reaction is mild and episodic. But in others, it is extreme and frequent; they can consume 6, 7, 8 thousand calories in a single day. This syndrome of binge eating has attracted much attention among psychologists for a long time; and now neurobiologists have taken notice as well.

What’s going on?

I remember from my marathon racing days that at about 18-20 miles I would hit a psychological low. I would be dragging my feet, having lost my motivation to make a new personal best, struggling with my rationalizations that I should just quit, even vowing to myself to never again engage in this idiotic effort. But then I would pop something sweet (called Goo) into my mouth, and literally within a minute or two I would undergo a radical change: full of energy, motivated to pick up the pace, almost euphoric—I would sprint to the finish line. What an exhilarating experience! I didn’t waste any time registering for the next event.

Was it the extra shot of energy that caused the turnaround? Although this is the belief among runners, it couldn’t even begin to account for it. First, such an immediate effect could not be explained by increase in calories; sugar takes longer to get absorbed through the gut (and Goo is formulated for slow release). Second, the amount of calories could not sustain a runner for more that a mile or two; the mood-elevating effect lasted for many more miles.

In a recent issue of Scientific American Mind Prof. Michael Macht of the University of Wuerzburg, Germany, examines this question. He cites the classic research by Jacob Steiner of the Hebrew University of Jerusalem, which showed that a liking for sweet tastes is innate. When Steiner gave newborns a sugar solution, the babies made sucking movements, licked their lips and relaxed their faces, looking satisfied. When given a bitter substance, the babies reacted with disgust, scrunching their eyebrows together and sticking out their tongues. Psychologist Elliott Blass of U. of Mass. Amherst found that a pacifier dipped in sugar solution lessened the pain of circumcision far more then an unsweetened one. The pain suppression occurred quickly, with a maximum effect achieved in 2 minutes. (My parents did even better: they dabbed sweet wine on my lips; my screams of protest turned into an angelic smile). Whatever the case may be—the time frame of two minutes is suggestive of a brain mechanism, rather than a digestive one.

Pathways of addiction

Princeton University Professor Bartley Hoebel and his coworkers made rats sugar-dependent using a regime common to addicting rats to alcohol, heroin, nicotine, and other addictive substances: they repeated for one to four weeks a schedule of fasting and intermittent sugar availability. The rats gradually tripled their sugar intake and learned to binge on the sugar as soon as it was offered to them. In the sugar-addled brains of these rats they detected a sharp increase in the neurotransmitter dopamine, specifically in the reward system. This is exactly the response shown by animals and humans addicted to drugs. What caused this rise was not related to digestion of the sugar—it was present even when the investigators removed the sugar from the stomachs of the rats using an implanted fistula. Most likely, the rise in dopamine was related to the sweet taste of the sugar.

How can binge eating be controlled?

Certain drugs inhibit craving in addicts. For instance, the drug Naloxone is widely used in counteracting intoxication with morphine-based drugs. Interestingly, Naloxone also causes suppression of appetite. I am not familiar with any drug trial that is aimed to specifically suppress binge eating. But who needs drugs? This is like fighting fire with fire.

Stanford psychologist Christy Telch and her colleagues experimented with 44 women with binge-eating disorder. Some received no treatment (the control group), whereas others underwent so-called dialectical-behavior therapy or DBT. In this Marxist-sounding therapy the subjects learned to deal with negative emotions in ways other than eating, Over 20 sessions, a therapist explained the genesis and role of emotions and taught the women strategies for coping with stress, among other tactics.

Results: by the end of the experiment, the women who had DBT were having many fewer eating attacks than the control subjects, and 89% of those treated had stopped binge eating. Six months later 56% of the treated women were still abstinent.

Yet again, we are seeing the inextricably intimate connection between body, brain and behavior. So I am off to the kitchen for a piece of superb Scharffenberger chocolate to celebrate this axis of bliss.

Dov Michaeli MD, Ph.D is in the Biotech industry, and loves chocolate.

By Dov Michaeli MD, Ph.D

Leptin is a hormone secreted from fat cells that provides information to the brain about energy stores. If energy stores are abundant, circulating levels of leptin are high, and the brain’s response is reduced food intake. On the other hand, in the fasted state leptin levels are low, and the response is increased food intake. It had been known that the regions of the brain where leptin exerts its influence are the nucleus accumbens and the associated nerve bundles called the striatum, regions where the reward/pleasure centers are located (and are the seat of addiction as well). However, there is little or no information about how these  brain centers integrate leptin’s signal with the rewarding properties of food.

Now a group of scientists from Cambridge university in the UK provided the missing link. In a paper published recently in Science they report on a study done on a 14 year-old boy and a 19 year-old girl who suffered from a very rare condition of leptin deficiency. This condition causes hyperphagia or excessive eating and gross obesity. But when they were injected with synthetic leptin eating was reduced to about normal levels. The investigators used fMRI (functional MRI) to visualize the nucleus accumbens and striatum. They presented the subjects with visual images of food, and for control-- visual images of non-food, in the leptin-deficient and leptin-treated states. They used a 10-cm visual analog scores to rate hunger, satiety, and the “liking” of the various food images.

And the results…

What they have shown is that leptin markedly affects neural responses to visual food stimuli; the appropriate reward centers showed markedly elevated blood flow, indicating increased metabolic activity in those regions. The responses to the questionnaire rating hunger, satiety and “liking” of the food images indicated that leptin did not affect the “liking” but rather the “wanting” of food. In the leptin-deficient state, images of well-liked foods engendered a greater wanting response, even when the subject had just been fed. After leptin treatment, well-liked food images engendered this response only in the fasted state. Thus, wanting of food appears to drive the correlation between activation of the reward centers and liking.

Why is it important?

At first blush, the whole exercise looks like splitting hairs: what difference is there between wanting and liking a food? My son used to hate anything that lived in water. But when he was famished enough he wolfed down a salmon steak and asked for more. In neurobiological terms, his low leptin level told his brain: you want this fish, liking it is not an issue right now. Which reminds me of a conversation I had with an orthodox rabbi about arranged marriages. What about love, I asked. That will come after the wedding, he answered.

From an evolutionary point of view it makes a lot of sense. Roaming the Savannah in search of food after several days of fasting there is no advantage in being too choosy; just give me that piece of meat, and I don’t care where it came from. I suspect that liking a certain food is a relatively recent addition to our behavioral repertoire, after the invention of agriculture about 10,000 years ago and the availability of reliable and abundant supply of food. Before that we didn’t eat—we devoured.

Dov Michaeli MD, Ph.D is in the Biotech industry, and he really likes good food.

By Dov Michaeli MD, Ph.D

No, I haven’t become a “new age”, “positive thinking”, “psychic energy” guy. I have seen a lot of willpower, grit and optimism overcome physical limitations—but that does not correct a physical limitation. Wouldn’t a way to change the brain’s perception of pain, or alter the brain’s pathways that determine an addictive behavior be a better solution than the panoply of drugs that we addle our brain with?

Technology to the rescue

One of the advantages of living in Northern California is being plugged in to the new and emergent technologies that are all around us. Superb universities that are incubators of revolutionary ideas, startup companies budding all over the place like mushrooms after the rain, many of them folding, other going on to do great and wonderful things (heard about the latest one? It has a funny name, something like Google)—what an exciting time and place to live in.

So it was really just a question of time before somebody took a stab at exploiting the brain’s plasticity (its adaptability or capacity to change) in order to deal with medical and psychiatric problems. Indeed, several startups are already hard at work doing just that.

How do they do it?

The technique of fMRI or functional MRI measures the blood flow in different regions of the brain, and displays it on a screen. This is how radiologists can determine areas in the brain that are metabolically hyperactive (pain perception, hunger, thinking) or hypoactive (stroke, some tumors). But now, a few companies are developing ‘real-time fMRI’, which means that you can view your own brain MRI in, well, real time. And that opens up some exciting possibilities.

Remember the old EEG (electroencephalogram) biofeedback technology? Subjects would be hooked up with electrodes which measure electrical feedback across the brain. They would then use a visual representation of the brain waves to control their blood pressure, for instance, using techniques of biofeedback such as meditation or visualization. The results were encouraging but were not translated to clinical use.

The new fMRI technique actually shows the subject which areas of the brain have increased blood flow if they suffer from chronic pain, for instance. The patient lies inside the scanner and watches a computer-generated flame projected on the screen of virtual-reality goggles; the flame’s intensity reflects the neural activity of regions of the brain involved in the perception of pain. Most people can control the flame’s intensity by concentrating and using visualization techniques. One could imagine bathing the neurally active region with a soothing drug, or dousing the area with a cold liquid, the flame would wane and patient would feel relief of the pain. Amazing but true.

This is actually an old concept. Paul Eckman, a professor of psychiatry at UCSF, wrote extensively about the mutual interaction between the body and the brain. We know, for instance, that a happy thought brings a smile to our face. But he showed that conversely, using the facial muscles involved in smiling activates the pleasure/reward centers in the brain. Result: you feel happy for no reason at all. Just try smiling every morning, or singing “Oh, what a beautiful morning” when you get out of bed, and you’d be amazed at the results. I read a few years ago about an Indian man who would go out to the park, and would laugh out loud without any reason. He claimed that it put him in a happy frame of mind for the rest of the day. Soon, other people joined him. They formed a laughing club, meeting daily in the park. This laughter became infectious, and thousands of people around the globe formed their own clubs. Sounds wacky, but it works, and it has a neurobiological basis. Try it!

The possibilities are mind boggling

What else can be controlled?

• I already mentioned the craving for drugs; addiction should be eminently amenable to this technique, since it is restricted to distinct brain regions.
• Hunger and feeding control.
• Psychiatric diseases such as depression.
• Behavioral disorders, such as uncontrolled anger, fear, phobias.
• How about stroke? Recent experiments have shown that by forcing stroke patients to use their paralyzed limb rather than the functional one, they begin to regain function. Underlying this “miracle” is the capacity of the brain to adapt and generate new pathways to serve the functions of the damaged ones. One problem with these experiments is that improvement is painfully slow and uneven. It is quite plausible the visualization of the new areas, which should have increased blood flow, could improve the outcome of these experiments.

I am sure that assorted libertarians and privacy watchdogs will warn about the sinister possibilities of this kind of brain control. Frankly my dear reader, I don’t…Just smile and be happy.

Dov Michaeli MD, Ph.D is in the biotech industry and is engaged in development of pain control medication.

By Dov Michaeli MD, Ph.D

In a September 6 posting (Bipoar Diagnosis in Children: another epidemic?) I posited that because of the fuzzy definition of this and other psychiatric disorders, physicians tend to take an expansive view of the disorder, for a variety of reasons (not the least of which is monetary)—resulting in a forty (40!) fold increase in diagnosis in eight years, from 1994-1995 to 2002-2003. One week later, the New York Times of September 13 published an excellent op-ed by Sally Satel, a psychiatrist and resident scholar at the American Enterprise Institute and co-author of “One Nation Under Therapy”, which deals with the same problem.

“ We still don't know how much of this increase represents long-overdue care of mentally ill youth and how much comes from facile labeling of youngsters who are merely irritable and moody”.

Dr. Satel point out that Part of the confusion stems from the lack of a discrete definition of juvenile bipolar illness in the diagnostic manual. But there is a deeper problem: despite the great progress being made in neuroscience, we still don't have a clear picture of the brain mechanisms underlying bipolar illness -- or most other mental illnesses . ”

Fair enough. To borrow a baseball metaphor (I can’t believe I am using it) we are at the beginning of the first inning; we barely scratched the surface of this enormously complex organ, and understand even less how it works and why it malfunctions. So yes, we cannot define a disease with the same accuracy as we define, say, a myocardial infarction or a bacterial infection. But surely we could do better. Even in the days when the pathophysiology underlying a heart attack was not known, the symptoms were clearly defined and diagnosis was made quite reliably.

Part of the problem of relying on symptoms to define a disease is that many patients meet several diagnostic definitions at once. Roughly half of children with a diagnosis of ADHD, for example, also have symptoms that fit the definition of bipolar disorder. Do these patients actually suffer more than one illness, or do they just appear to? Conversely, very diverse patients often qualify for the same diagnosis. Children with depression, anxiety, irritability, moodiness or plain exuberant personality can all fit the diagnosis of ADHD.

What’s to be done?

Earlier this summer, the American Psychiatric Association announced that a 27-member panel will update its official diagnostic handbook, the Diagnostic and Statistical Manual of Mental Disorders. The fifth edition, which is scheduled to come out in 2012, is likely to add new mental illnesses and refine some existing ones. Dr. Satel proposes to define each disease as a continuum, allowing the physician to make a more refined and more nuanced diagnosis. Excellent idea! But I would say: not enough. I would add to each diagnosis several illustrative case studies, maybe in the form of an accompanying workbook. Such case studies could describe the classical presentations of a given disorder as well as its extremes, both mild and severe. This would illustrate the breadth of a diagnosis, and hopefully avoid much of the confusion that is common today.

The current state of psychiatric diagnoses reminds me of the Talmudic proverb, “the breach invites the thief”, by which it meant that the lack of clear definition and boundaries invites all sorts of bad behavior. Hopefully, the new Manual will close that breach.

Dov Michaeli MD, Ph.D is in the Biotech industry.

By Dov Michaeli MD, Ph